The long-term objective of this IRPG research program is to identify the genes and the neurobiological substrates underlying alcohol-seeking behavior through studies in animal models. In 1976, we began the selective breeding of rat lines for high and low alcohol consumption/preference from a foundation stock of Wistar rats. The resultant preferring P line was subsequently shown to satisfy the criteria for an animal-model of alcoholism. Comparisons of the P and the nonpreferring NP lines have revealed innate neurobiological differences between the lines as well as differences in responses to alcohol. Such gains in neurobiological knowledge have led to promising avenues of medications development for alcoholism. In 1984, we began the selection of the HAD (high-alcohol-drinking) and LAD (low-alcohol-drinking) lines from the genetically heterogeneous N/Nih rat. They are now at about the S2O generation. The specific aims of this research project (IRPG 1) in the next 5 years will be: l) to continue developing the replicate HAD1/LAD1 and HAD2/LAD2 lines to stable selection limits; 2) to ascertain that selection limit has been reached by means of reverse selection and inbreeding; and 3) to cryopreserve embryos from the HAD and LAD lines, when they have reached selection limits. The HAD and LAD animals will then be compared to ascertain whether the behavioral, neurochemical and neuroanatomical differences found between-the P and NP lines are- seen also between the HAD and LAD lines. These studies will be performed in collaboration with IRPGs 5, 7 and 8. The-behavioral measures (specific aim 4) will include spontaneous motor activity, anxiety, operant responding to ethanol, the anxiolytic effect of ethanol, ethanol-induced aversion, and tolerance to the motor-impairment and aversive effects of- ethanol. The neurochemical measures (specific aim 5) will include the brain regional contents of serotonin (5HT), dopamine (DA) and their metabolites, and the regional densities of 5HT, DA, GABA, NMDA, opioid, and nicotinic receptors. The neuroanatomical measures (specific aim 6) will be DA and 5HT fiber densities in selected brain regions. Finally, genetic correlations between alcohol consumption and other behavioral associations of alcohol preference discovered in the P/NP lines will be ascertained in the F2 offspring of inbred P and NP rats, and QTL napping of alcohol preference and correlated traits will be performed in these F2 animals (specific aim 7), in collaboration with IRPG 2.